Sodium channel mutations and susceptibility to heart failure and atrial fibrillation

Timothy Mark Olson, Virginia V. Michels, Jeffrey D. Ballew, Sandra P. Reyna, Margaret L. Karst, Kathleen J. Herron, Steven C. Horton, Richard J. Rodeheffer, Jeffrey L. Anderson

Research output: Contribution to journalArticle

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Abstract

Context: Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. Objectives: To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. Design, Setting, and Participants: Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. Main Outcome Measure: Correlation of identified mutations with cardiac phenotype. Results: Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years). Conclusions: Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.

Original languageEnglish (US)
Pages (from-to)447-454
Number of pages8
JournalJournal of the American Medical Association
Volume293
Issue number4
DOIs
StatePublished - Jan 26 2005

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Sodium Channels
Dilated Cardiomyopathy
Atrial Fibrillation
Heart Failure
Mutation
Genes
Phenotype
Contractile Proteins
Missense Mutation
Cytoskeleton
Echocardiography
Cardiac Arrhythmias
Heart Diseases
Potassium
Electrocardiography

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Olson, T. M., Michels, V. V., Ballew, J. D., Reyna, S. P., Karst, M. L., Herron, K. J., ... Anderson, J. L. (2005). Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. Journal of the American Medical Association, 293(4), 447-454. https://doi.org/10.1001/jama.293.4.447

Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. / Olson, Timothy Mark; Michels, Virginia V.; Ballew, Jeffrey D.; Reyna, Sandra P.; Karst, Margaret L.; Herron, Kathleen J.; Horton, Steven C.; Rodeheffer, Richard J.; Anderson, Jeffrey L.

In: Journal of the American Medical Association, Vol. 293, No. 4, 26.01.2005, p. 447-454.

Research output: Contribution to journalArticle

Olson, TM, Michels, VV, Ballew, JD, Reyna, SP, Karst, ML, Herron, KJ, Horton, SC, Rodeheffer, RJ & Anderson, JL 2005, 'Sodium channel mutations and susceptibility to heart failure and atrial fibrillation', Journal of the American Medical Association, vol. 293, no. 4, pp. 447-454. https://doi.org/10.1001/jama.293.4.447
Olson, Timothy Mark ; Michels, Virginia V. ; Ballew, Jeffrey D. ; Reyna, Sandra P. ; Karst, Margaret L. ; Herron, Kathleen J. ; Horton, Steven C. ; Rodeheffer, Richard J. ; Anderson, Jeffrey L. / Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. In: Journal of the American Medical Association. 2005 ; Vol. 293, No. 4. pp. 447-454.
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abstract = "Context: Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. Objectives: To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. Design, Setting, and Participants: Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. Main Outcome Measure: Correlation of identified mutations with cardiac phenotype. Results: Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27{\%} had early features of DCM (mean age at diagnosis, 20.3 years), 38{\%} had DCM (mean age at diagnosis, 47.9 years), and 43{\%} had atrial fibrillation (mean age at diagnosis, 27.8 years). Conclusions: Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.",
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AU - Olson, Timothy Mark

AU - Michels, Virginia V.

AU - Ballew, Jeffrey D.

AU - Reyna, Sandra P.

AU - Karst, Margaret L.

AU - Herron, Kathleen J.

AU - Horton, Steven C.

AU - Rodeheffer, Richard J.

AU - Anderson, Jeffrey L.

PY - 2005/1/26

Y1 - 2005/1/26

N2 - Context: Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. Objectives: To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. Design, Setting, and Participants: Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. Main Outcome Measure: Correlation of identified mutations with cardiac phenotype. Results: Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years). Conclusions: Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.

AB - Context: Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. Objectives: To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. Design, Setting, and Participants: Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. Main Outcome Measure: Correlation of identified mutations with cardiac phenotype. Results: Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years). Conclusions: Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.

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